ES2332226T3 - PHARMACEUTICAL COMPOSITIONS THAT INCLUDE DROSPIRENONE. - Google Patents
PHARMACEUTICAL COMPOSITIONS THAT INCLUDE DROSPIRENONE. Download PDFInfo
- Publication number
- ES2332226T3 ES2332226T3 ES05076969T ES05076969T ES2332226T3 ES 2332226 T3 ES2332226 T3 ES 2332226T3 ES 05076969 T ES05076969 T ES 05076969T ES 05076969 T ES05076969 T ES 05076969T ES 2332226 T3 ES2332226 T3 ES 2332226T3
- Authority
- ES
- Spain
- Prior art keywords
- composition
- drospirenone
- composition according
- pharmaceutical
- estrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960004845 drospirenone Drugs 0.000 title claims abstract description 63
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 title claims abstract description 63
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 229940011871 estrogen Drugs 0.000 claims abstract description 17
- 239000000262 estrogen Substances 0.000 claims abstract description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- 238000004090 dissolution Methods 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 239000003981 vehicle Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 210000004696 endometrium Anatomy 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000006186 oral dosage form Substances 0.000 claims description 4
- 238000004806 packaging method and process Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 238000007922 dissolution test Methods 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 206010020718 hyperplasia Diseases 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 150000005846 sugar alcohols Chemical class 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 239000000583 progesterone congener Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- -1 mannitol Chemical compound 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000000186 progesterone Substances 0.000 description 4
- 229960003387 progesterone Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- 206010024870 Loss of libido Diseases 0.000 description 2
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- 208000001132 Osteoporosis Diseases 0.000 description 2
- 206010033557 Palpitations Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 206010037180 Psychiatric symptoms Diseases 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000027758 ovulation cycle Effects 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010006179 Breast atrophy Diseases 0.000 description 1
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- 208000026310 Breast neoplasm Diseases 0.000 description 1
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- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010027940 Mood altered Diseases 0.000 description 1
- 206010027951 Mood swings Diseases 0.000 description 1
- 229920002367 Polyisobutene Polymers 0.000 description 1
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- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010071018 Urogenital atrophy Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
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- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000001327 anti-mineralocorticoid effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
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- 201000008275 breast carcinoma Diseases 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
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- 239000000839 emulsion Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- GCKFUYQCUCGESZ-BPIQYHPVSA-N etonogestrel Chemical compound O=C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 GCKFUYQCUCGESZ-BPIQYHPVSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229920002313 fluoropolymer Polymers 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000003152 gestagenic effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 201000001441 melanoma Diseases 0.000 description 1
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- 206010029410 night sweats Diseases 0.000 description 1
- 230000036565 night sweats Effects 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
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- 230000017105 transposition Effects 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- A—HUMAN NECESSITIES
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Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
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- Diabetes (AREA)
- Biomedical Technology (AREA)
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- Neurology (AREA)
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- Dermatology (AREA)
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- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
Una composición farmacéutica que comprende drospirenona junto con un vehículo o excipiente farmacéuticamente aceptable, en que dicha composición no contiene ningún estrógeno y en que dicha drospirenona está en una forma micronizada.A pharmaceutical composition comprising drospirenone together with a pharmaceutically acceptable carrier or excipient, in which said composition does not contain any estrogen and in which said drospirenone is in a micronized form.
Description
Composiciones farmacéuticas que comprenden drospirenona.Pharmaceutical compositions comprising Drospirenone
La presente invención se refiere a una composición farmacéutica que comprende drospirenonaThe present invention relates to a pharmaceutical composition comprising drospirenone
La drospirenona se conoce desde el documento DE 26 52 761, en el que se describe su uso.Drospirenone is known from the DE document 26 52 761, in which its use is described.
En el documento DE 30 22 337 se describe la actividad de tipo gestágeno de la drospirenona, y su utilidad consiguiente como agente anticonceptivo a unos niveles de dosis de 0,5-50 mg.Document DE 30 22 337 describes the Drospirenone gestagenic activity, and its usefulness consequently as a contraceptive agent at dose levels of 0.5-50 mg
El uso y el papel de los progestágenos en formas opuestas de terapia hormonal de sustitución se han estudiado por la comunidad científica (Lobo R.A., 1992; Sobel N.B., 1994), como lo han sido los regímenes que comprenden estrógenos y progestágenos (Corson S.L., 1993; Jones K.P., 1992).The use and role of progestogens in forms Opposite hormone replacement therapy have been studied by the scientific community (Lobo R.A., 1992; Sobel N.B., 1994), as have been the regimes that comprise estrogens and progestogens (Corson S.L., 1993; Jones K.P., 1992).
En el documento PCT/EP94/02997 se describe el uso de una preparación para terapia de sustitución y para anticoncepción oral, que comprende al menos un progestágeno y al menos un estrógeno, en la que la dosis del estrógeno varía con una periodicidad tal que se evita sustancialmente la pérdida de sangre.Document PCT / EP94 / 02997 describes the use of a preparation for replacement therapy and for oral contraception, which comprises at least one progestogen and at minus an estrogen, in which the dose of estrogen varies with a periodicity such that the loss of blood.
La invención se refiere, en un primer aspecto, a una composición farmacéutica que comprende drospirenona junto con un vehículo o excipiente farmacéuticamente aceptable, en el que dicha composición no contiene ningún estrógeno y en el que dicha drospirenona está en una forma micronizada.The invention relates, in a first aspect, to a pharmaceutical composition comprising drospirenone together with a pharmaceutically acceptable carrier or excipient, in which said composition does not contain any estrogen and in which said Drospirenone is in a micronized form.
En un segundo aspecto, la presente invención se refiere a una composición farmacéutica que comprende drospirenona junto con un vehículo o excipiente farmacéuticamente aceptable, en el que dicha composición no contiene ningún estrógeno y en el que dicha drospirenona está en una forma que tiene una superficie específica mayor que 10.000 cm^{2}/g.In a second aspect, the present invention is refers to a pharmaceutical composition comprising drospirenone together with a pharmaceutically acceptable carrier or excipient, in which said composition does not contain any estrogen and in which said drospirenone is in a form that has a surface specific greater than 10,000 cm2 / g.
En un aspecto adicional, la presente invención se refiere a una composición farmacéutica que comprende drospirenona junto con un vehículo o excipiente farmacéuticamente aceptable, en el que dicha composición no contiene ningún estrógeno y en el que dicha drospirenona está en una forma que tiene una disolución rápida, de manera que al menos el 70% de dicha drospirenona se disuelve en 30 minutos cuando la composición se somete a un ensayo de disolución en 900 ml de agua a 37ºC usando el Método II de Paleta USP XXIII operado a una velocidad de agitación de 50 rpm.In a further aspect, the present invention refers to a pharmaceutical composition comprising drospirenone together with a pharmaceutically acceptable carrier or excipient, in which said composition does not contain any estrogen and in which said drospirenone is in a form that has a solution rapidly, so that at least 70% of said drospirenone is dissolves in 30 minutes when the composition is tested of solution in 900 ml of water at 37 ° C using Pallet Method II USP XXIII operated at a stirring speed of 50 rpm.
En un aspecto adicional incluso más particular, la presente invención se refiere a una composición farmacéutica que comprende partículas de soporte inertes que contienen drospirenona en su superficie, en el que dicha composición no contiene ningún estrógeno, y en el que al menos el 70% de dicha drospirenona se disuelve en 30 minutos cuando la composición se somete a un ensayo de disolución en 900 ml de agua a 37ºC usando el Método II de Paleta USP XXIII operado a una velocidad de agitación de 50 rpm.In an additional aspect even more particular, The present invention relates to a pharmaceutical composition that comprises inert support particles containing drospirenone on its surface, in which said composition does not contain any estrogen, and in which at least 70% of said drospirenone is dissolves in 30 minutes when the composition is tested of solution in 900 ml of water at 37 ° C using Method II of USP XXIII blade operated at a stirring speed of 50 rpm.
En un aspecto adicional todavía más particular, la presente invención se refiere a una preparación farmacéutica que consiste en un número de unidades de dosificación de acuerdo con la invención, envasadas por separado y que pueden retirarse individualmente, dispuestas en una unidad de envasado y destinadas a administración oral durante un período de al menos 21 días.In an additional aspect even more particular, The present invention relates to a pharmaceutical preparation that It consists of a number of dosage units according to the invention, packaged separately and can be removed individually, arranged in a packaging unit and intended for oral administration for a period of at least 21 days.
En todavía otro aspecto, la presente invención se refiere al uso de una composición de acuerdo con la invención para la preparación de un medicamento para proteger al endometrio de la hiperplasia o del cáncer.In yet another aspect, the present invention refers to the use of a composition according to the invention for the preparation of a medicine to protect the endometrium from hyperplasia or cancer.
Además, la presente invención se refiere al uso de una composición de acuerdo con la invención para la preparación de un medicamento para el tratamiento de la endometriosis.In addition, the present invention relates to the use of a composition according to the invention for the preparation of a medication for the treatment of endometriosis.
El uso de progesterona natural en terapia está limitado por la baja biodisponibilidad de la progesterona natural, incluso en forma micronizada. Significativamente, se ha encontrado que la terapia que comprende el uso de drospirenona como progestágeno es notablemente eficaz. La drospirenona (DRSP), un derivado 17-\alpha-espirolactona, es un progestágeno sintético que tiene un perfil fisiológico sorprendentemente similar a la progesterona, pero una biodisponibilidad notablemente mejor. Es el primer progestágeno sintético en tener un perfil farmacológico similar a la progesterona en cuanto a su actividad antiestrogénica, antiandrogénica, y tiene actividad antimineralocorticoide.The use of natural progesterone in therapy is limited by the low bioavailability of natural progesterone, even in micronized form. Significantly, it has been found that the therapy comprising the use of drospirenone as Progestogen is remarkably effective. Drospirenone (DRSP), a 17-? -spirolactone derivative, It is a synthetic progestin that has a physiological profile surprisingly similar to progesterone, but a remarkably better bioavailability. It is the first progestogen synthetic in having a pharmacological profile similar to the progesterone in terms of its anti-estrogenic activity, antiandrogenic, and has antimineralocorticoid activity.
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Aparte de la propia sustancia activas, se prevé que se pueda emplear en la presente composición un éster o profármaco de drospirenona, por ejemplo una oxiiminopregnano-carbolactona, como se describe en el documento WO 98/24801.Apart from the active substance itself, it is expected that an ester or drospirenone prodrug, for example a oxyiminopregnan-carbolactone, as described in WO 98/24801.
Una realización interesante de la invención comprende una composición en la que la drospirenona (DRSP) está en forma micronizada.An interesting embodiment of the invention comprises a composition in which drospirenone (DRSP) is in micronized form
La drospirenona, que se puede preparar sustancialmente como se describe, p.ej., en los documentos US 4.129.564 o WO 98/06738, es una sustancia poco soluble en agua y tampones acuosos a diversos valores de pH. Adicionalmente, la drospirenona sufre transposición para dar un isómero inactivo en condiciones ácidas, y se hidroliza en condiciones alcalinas. Para asegurar una biodisponibilidad satisfactoria del compuesto, el mismo se proporciona por tanto ventajosamente en una forma que favorece su disolución rápida.Drospirenone, which can be prepared substantially as described, eg, in US documents 4,129,564 or WO 98/06738, is a substance that is poorly soluble in water and aqueous buffers at various pH values. Additionally, the drospirenone undergoes transposition to give an inactive isomer in acidic conditions, and hydrolyzes under alkaline conditions. For ensure satisfactory bioavailability of the compound, the same it is therefore advantageously provided in a manner that favors Its rapid dissolution.
Se ha encontrado que cuando se proporciona drospirenona en forma micronizada en una composición farmacéutica, se produce una disolución rápida in vitro del compuesto activo a partir de la composición. Una sustancia micronizada es aquella tal que un lote de ensayo (aprox. 200 mg) de las partículas, aquí partículas de drospirenona, tiene una superficie específica mayor que 10.000 cm^{2}/g, y tiene la siguiente distribución de tamaños de partículas para drospirenona, según se determina al microscopio: no más de 2 partículas en un lote dado (aprox. 200 mg) tienen un diámetro mayor que 30 \mum, y preferiblemente \leq 20 partículas con un diámetro de \geq 10 \mum y \leq 30 \mum. La expresión "disolución rápida" se define como la disolución de al menos 70% durante alrededor de 30 minutos, en particular al menos 80% durante alrededor de 20 minutos, de drospirenona a partir de una preparación de comprimidos que contiene 3 mg de drospirenona en 900 ml de agua a 37ºC, determinada por el Método de la Paleta USP XXIII utilizando un aparato de ensayo de disolución USP 2, a 50 rpm).It has been found that when drospirenone is provided in micronized form in a pharmaceutical composition, a rapid in vitro dissolution of the active compound from the composition occurs. A micronized substance is one such that a test lot ( approx . 200 mg) of the particles, here drospirenone particles, has a specific surface area greater than 10,000 cm2 / g, and has the following particle size distribution for drospirenone, as determined under a microscope: no more than 2 particles in a given batch (approx. 200 mg) have a diameter greater than 30 µm, and preferably ≤ 20 particles with a diameter of ≥ 10 µm and leq 30 µm. The term "rapid dissolution" is defined as the dissolution of at least 70% for about 30 minutes, in particular at least 80% for about 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37 ° C, determined by the USP XXIII Paddle Method using a USP 2 dissolution test apparatus, at 50 rpm).
Como una alternativa a proporcionar la drospirenona en forma micronizada, es posible disolverla en un disolvente adecuado, p.ej. metanol o acetato de etilo, y pulverizarla sobre la superficie de partículas de vehículo inertes, seguido de la incorporación en la composición de las partículas que contienen drospirenona en su superficie.As an alternative to providing the Drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, eg methanol or ethyl acetate, and spray it on the surface of inert vehicle particles, followed by the incorporation into the composition of the particles that They contain drospirenone on their surface.
Sin pretender quedar limitados por ninguna teoría particular, parece ser que la velocidad de disolución in vitro de la drospirenona está relacionada con la velocidad de disolución in vivo, lo que da como resultado una rápida absorción de drospirenona in vivo en la administración oral del compuesto. Esto constituye una ventaja, dado que se reduce sustancialmente la isomerización del compuesto en el medio gástrico, y/o la hidrólisis en el intestino, conduciendo a una elevada biodisponibilidad del compuesto.Without pretending to be limited by any particular theory, it seems that the in vitro dissolution rate of drospirenone is related to the dissolution rate in vivo , which results in a rapid absorption of drospirenone in vivo on oral administration of the compound. This constitutes an advantage, since the isomerization of the compound in the gastric medium, and / or the hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound.
Para obtener una velocidad de disolución más rápida, se prefiere incluir vehículos o excipientes, que actúan para favorecer la disolución de la sustancia activa. Ejemplos de tales vehículos y excipientes incluyen sustancias que son fácilmente solubles en agua, tales como derivados de celulosa, carboximetilcelulosa, hidroxipropilcelulosa, hidroxipropilmetilcelulosa, almidón gelificado, gelatina o polivinilpirrolidona. En particular, se adelanta que la polivinilpirrolidona puede ser particularmente útil para favorecer la disolución.To obtain a dissolution rate more fast, it is preferred to include vehicles or excipients, which act to favor the dissolution of the active substance. Examples of such vehicles and excipients include substances that are easily soluble in water, such as cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it is anticipated that the Polyvinylpyrrolidone may be particularly useful for promoting dissolution
La dosis de la drospirenona en cada composición es preferiblemente tal que protege al endometrio de los efectos adversos de un estrógeno. La DRSP, en dosis suficientes, se puede usar como un oponente del estrógeno, para proteger al endometrio de la hiperplasia o del cáncer.The dose of drospirenone in each composition it is preferably such that it protects the endometrium from the effects adverse effects of an estrogen. DRSP, in sufficient doses, can be use as an estrogen opponent, to protect the endometrium from hyperplasia or cancer.
Sin embargo, en algunos casos, la dosis de DRSP puede ser suficiente para estabilizar el ciclo menstrual y la pauta de hemorragia. La producción de tejido adiposo de estrógeno puede ser tal que no se requiera ningún estrógeno para estabilizar el ciclo menstrual y la pauta de hemorragia. Además, en ciertas realizaciones, cuando la mujer sufre otros trastornos no compatibles con el uso de una fuente exógena de estrógeno (tal como para las contraindicaciones absolutas de hepatopatías graves y embarazo, o para las contraindicaciones relativas de carcinoma del endometrio y endometriosis, carcinoma de mama, tromboembolia venosa, hipertensión, diabetes mellitus, otoesclerosis y melanoma), en la composición no hay ningún estrógeno. En tales realizaciones, la dosis de DRSP puede ser tal que se alivie el trastorno, la enfermedad o el síntoma.However, in some cases, the dose of DRSP it may be enough to stabilize the menstrual cycle and the pattern of hemorrhage The production of estrogen adipose tissue can be such that no estrogen is required to stabilize the menstrual cycle and bleeding pattern. In addition, in certain realizations, when the woman suffers other disorders not compatible with the use of an exogenous source of estrogen (such as for the absolute contraindications of severe liver diseases and pregnancy, or for relative contraindications of carcinoma of the endometrium and endometriosis, breast carcinoma, venous thromboembolism, hypertension, diabetes mellitus, otosclerosis and melanoma), in the composition there is no estrogen. In such embodiments, the dose of DRSP may be such that the disorder is relieved, the disease or symptom
En realizaciones preferidas, la dosis de DRSP
corresponde a 15 hasta 70 mg por ciclo, tal como 20 hasta 60 mg por
ciclo, particularmente 40 hasta 60 mg por ciclo. La duración del
ciclo puede variar de 21 a 31 días. Visto de otro modo, una
composición puede comprender una cantidad de DRSP que corresponde a
una dosis diaria que oscila desde 0,25 hasta 10, tal como alrededor
de 0,25 hasta 8, 0,25 hasta 6, 0,25 hasta 5, 0,5 hasta 4,5, 1 hasta
4, y 1,5 hasta
3,5 mg.In preferred embodiments, the dose of DRSP corresponds to 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, particularly 40 to 60 mg per cycle. The duration of the cycle can vary from 21 to 31 days. Viewed another way, a composition may comprise an amount of DRSP corresponding to a daily dose ranging from 0.25 to 10, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to
3.5 mg
En otras realizaciones, la dosis de DRSP es suficiente para tratar sofocos, ataques de transpiración, palpitaciones, trastornos del sueño, cambios del ánimo, nerviosismo, ansiedad, mala memoria, pérdida de confianza, pérdida de libido, mala concentración, reducción de la energía, vigor reducido, irritabilidad, atrofia urogenital, atrofia de las mamas, enfermedad cardiovascular, cambios en la distribución del cabello, espesor del cabello, cambios en el estado de la piel, o para la prevención o tratamiento de osteoporosis.In other embodiments, the dose of DRSP is enough to treat hot flashes, perspiration attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, bad memory, loss of confidence, loss of libido, poor concentration, energy reduction, vigor reduced, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair distribution, hair thickness, changes in skin condition, or for the prevention or treatment of osteoporosis.
La dosis de DRSP puede depender del tratamiento, sea éste para la protección del endometrio, tal como la pauta de hemorragia, para la prevención o el tratamiento de la osteoporosis, para el tratamiento de los síntomas menopáusicos, tales como para la reducción del número, de la frecuencia y de la gravedad de los sofocos, transpiraciones nocturnas, cambios bruscos del ánimo con palpitaciones, insomnio y otros trastornos del sueño, cambios del ánimo, nerviosismo, ansiedad, mala memoria, pérdida de confianza, pérdida de libido, mala concentración, reducción de la energía, vigor reducido, e irritabilidad.The dose of DRSP may depend on the treatment, be this for endometrial protection, such as the pattern of hemorrhage, for the prevention or treatment of osteoporosis, for the treatment of menopausal symptoms, such as for the reduction of the number, frequency and severity of hot flashes, night sweats, sudden mood swings with palpitations, insomnia and other sleep disorders, changes in mood, nervousness, anxiety, bad memory, loss of confidence, loss of libido, poor concentration, energy reduction, reduced vigor, and irritability.
En realizaciones en las que la mujer está perimenopáusica, la dosis de DRSP puede depender del día del ciclo, esto es, si está en la fase preovuladora o posovuladora del ciclo, y cuán avanzada está en cada fase. En realizaciones en las que la mujer está posmenopáusica, o incluso premenopáusica, la dosis de DRSP puede depender del tiempo desde la última menstruación.In realizations in which the woman is perimenopausal, the dose of DRSP may depend on the day of the cycle, that is, if it is in the pre-ovulation or post-ovulation phase of the cycle, and How advanced it is in each phase. In embodiments in which the woman is postmenopausal, or even premenopausal, the dose of DRSP may depend on the time since the last menstruation.
En ciertas realizaciones de la invención, el medicamento se administra en forma de un número de unidades de dosificación envasadas por separado y que pueden retirarse individualmente, dispuestas en una unidad de envasado y destinadas a administración oral durante un período de al menos 21 días, tal como al menos 28 días, tal como al menos 30 ó 31 días. En tales realizaciones, la dosis de DRSP puede ser la misma dentro de cada unidad de dosificación, o puede variar. En realizaciones en las que la cantidad de DRSP en la unidad de dosificación varía según la fase o el día dentro del periodo de al menos 21 días, tal como al menos 28 días, en el que dicha unidad de dosificación se va a administrar, tales composiciones, métodos de tratamiento y preparaciones se denominan de múltiples fases.In certain embodiments of the invention, the medication is given in the form of a number of units of Dosage packaged separately and can be withdrawn individually, arranged in a packaging unit and intended to oral administration for a period of at least 21 days, such at least 28 days, such as at least 30 or 31 days. In such embodiments, the dose of DRSP may be the same within each dosage unit, or may vary. In embodiments in which the amount of DRSP in the dosage unit varies according to the phase or day within the period of at least 21 days, such as at minus 28 days, in which said dosage unit is going to administer, such compositions, treatment methods and Preparations are called multi-phase.
La composición de la unidad de dosificación se puede formular de cualquier manera convencional en la técnica farmacéutica. En particular, como se ha indicado anteriormente, la composición se puede formular mediante un método que comprende proporcionar drospirenona en forma micronizada en dicha forma de dosificación unitaria, o pulverizado a partir de una disolución sobre partículas de un vehículo inerte en mezcla con uno o más excipientes farmacéuticamente aceptables, que favorecen la disolución de la drospirenona, a fin de favorecer una disolución rápida de drospirenona en el caso de la administración oral. Ejemplos de excipientes adecuados incluyen cargas, p.ej. azúcares tales como lactosa, glucosa o sacarosa, alcoholes de azúcares tales como manitol, un almidón tal como almidón de maíz o de patata, o almidón modificado, lubricantes tales como talco o estearato de magnesio, y aglutinantes tales como polivinilpirrolidona, derivados de celulosa, carboximetil-celulosa, hidroxipropil-celulosa, hidroxipropilmetil-celulosa, metilcelulosa o gelatina, para preparar formas de dosificación oral tales como comprimidos, pastillas o cápsulas. Los comprimidos se pueden recubrir convenientemente con un agente adecuado formador de película, p.ej. hidroxipropilmetil-celulosa. La presente composición se puede formular también en forma líquida, p.ej. como disoluciones, suspensiones o emulsiones, junto con diluyentes o excipientes convencionales de una manera conocida per se en la técnica farmacéutica.The composition of the dosage unit can be formulated in any conventional manner in the pharmaceutical art. In particular, as indicated above, the composition may be formulated by a method comprising providing drospirenone in micronized form in said unit dosage form, or pulverized from a solution on particles of an inert vehicle in admixture with one or more Pharmaceutically acceptable excipients, which favor the dissolution of drospirenone, in order to favor a rapid dissolution of drospirenone in the case of oral administration. Examples of suitable excipients include fillers, eg sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, a starch such as corn or potato starch, or modified starch, lubricants such as talc or magnesium stearate , and binders such as polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose or gelatin, to prepare oral dosage forms such as tablets, pills or capsules. The tablets may conveniently be coated with a suitable film-forming agent, eg hydroxypropylmethyl cellulose. The present composition can also be formulated in liquid form, eg as solutions, suspensions or emulsions, together with conventional diluents or excipients in a manner known per se in the pharmaceutical art.
Una unidad de envasado que comprende las unidades de dosificación diaria descritas anteriormente se puede preparar de una manera análoga a la de la fabricación de otros anticonceptivos orales o regímenes de sustitución hormonal. Ésta puede ser, por ejemplo, un paquete de blíster convencional, o cualquier otra forma conocida para este propósito, por ejemplo un envase que comprende el número apropiado de unidades de dosificación (en este caso al menos 28, o para aplicaciones particulares, un múltiplo de 28) en un paquete de blíster herméticamente cerrado con un respaldo de cartón, cartulina, hoja metalizada o plástico, y encerrado en una cubierta adecuada. Cada envase de blíster puede estar numerado o marcado convenientemente de cualquier otro modo.A packaging unit comprising the Daily dosage units described above can be prepare in a manner analogous to the manufacturing of others oral contraceptives or hormone replacement regimens. This it can be, for example, a conventional blister pack, or any other form known for this purpose, for example a package comprising the appropriate number of dosage units (in this case at least 28, or for particular applications, a multiple of 28) in a tightly sealed blister pack with a cardboard, cardboard, metallic or plastic sheet backing, and enclosed in a suitable cover. Each blister pack can be numbered or conveniently marked from any other mode.
Se contempla también que la presente composición se pueda encontrar en forma de una formulación parenteral, tal como un implante subcutáneo, o una formulación transdérmica. Para la fabricación de implantes, el agente activo se puede formular convenientemente junto con uno o más polímeros que se erosionan o degradan gradualmente durante su uso, p.ej. polímeros de silicona, etileno-acetato de vinilo, polietileno o polipropileno.It is also contemplated that the present composition can be found in the form of a parenteral formulation, such as a subcutaneous implant, or a transdermal formulation. For the Implant manufacturing, the active agent can be formulated conveniently together with one or more polymers that erode or gradually degrade during use, eg silicone polymers, ethylene-vinyl acetate, polyethylene or Polypropylene.
En lo que concierne a las formulaciones transdérmicas, éstas se pueden preparar en forma de matrices o membranas, o como formulaciones fluidas o viscosas en aceite o hidrogeles. Para los parches transdérmicos, se debería incluir un adhesivo que sea compatible con la piel, tal como poliacrilato, un adhesivo de silicona, o poliisobutileno, así como una lámina delgada hecha de, p.ej., polietileno, polipropileno, etileno-acetato de vinilo, poli(cloruro de vinilo), poli(cloruro de vinilideno) o poliéster, y una lámina delgada protectora separable hecha de, p.ej., poliéster o papel recubierto con silicona o un polímero fluorado. Para la preparación de disoluciones o geles transdérmicos, se puede usar agua o disolventes orgánicos, o mezclas de los mismos. Los geles transdérmicos pueden contener adicionalmente uno o más agentes de gelificación o espesantes adecuados, tales como silicona, goma de tragacanto, almidón o derivados de almidón, celulosa o derivados de celulosa, o poli(ácidos acrílicos) o derivados de los mismos. Las formulaciones transdérmicas pueden contener también convenientemente una o más sustancias que aumenten la absorción a través de la piel, tales como sales biliares o derivados de las mismas y/o fosfolípidos. Las formulaciones transdérmicas adecuadas se pueden preparar, por ejemplo, de una manera análoga a la descrita en el documento WO 94/04157 para 3-cetodesogestrel. Alternativamente, las formulaciones transdérmicas se pueden preparar según un método expuesto en, p.ej, BW Barry, "Dermatological Formulations, Percutaneous Absorption", Marcel Dekker Inc., Nueva York-Basilea, 1983, o YW Chien, "Transdermal Controlled Systemic Medications", Marcel Dekker Inc., Nueva York-Basilea, 1987.As regards the formulations transdermal, these can be prepared in the form of matrices or membranes, or as fluid or viscous formulations in oil or hydrogels For transdermal patches, a adhesive that is compatible with the skin, such as polyacrylate, a silicone adhesive, or polyisobutylene, as well as a sheet thin made of, eg, polyethylene, polypropylene, ethylene vinyl acetate, poly (chloride vinyl), poly (vinylidene chloride) or polyester, and a thin separable protective sheet made of, e.g., polyester or silicone coated paper or a fluorinated polymer. For the preparation of transdermal solutions or gels, can be used water or organic solvents, or mixtures thereof. Gels transdermal agents may additionally contain one or more agents of suitable gelling or thickeners, such as silicone, rubber tragacanth, starch or derivatives of starch, cellulose or derivatives of cellulose, or poly (acrylic acids) or derivatives thereof. The transdermal formulations may also conveniently contain one or more substances that increase absorption through the skin, such as bile salts or derivatives thereof and / or phospholipids Suitable transdermal formulations can be prepare, for example, in a manner analogous to that described in the WO 94/04157 for 3-ketodesogestrel. Alternatively, transdermal formulations can be prepare according to a method set forth in, e.g., BW Barry, "Dermatological Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York-Basel, 1983, or YW Chien, "Transdermal Controlled Systemic Medications", Marcel Dekker Inc., New York-Basel, 1987.
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| ES01900579T Expired - Lifetime ES2247054T3 (en) | 2000-01-18 | 2001-01-18 | PHARMACEUTICAL COMBINATION OF MICRONIZED DROSPIRENONE AND A STROGEN FOR HORMONAL REPLACEMENT THERAPY. |
Country Status (30)
| Country | Link |
|---|---|
| EP (2) | EP1257280B1 (en) |
| JP (2) | JP5128743B2 (en) |
| KR (2) | KR100747965B1 (en) |
| CN (2) | CN101934078A (en) |
| AT (2) | ATE442147T1 (en) |
| AU (3) | AU2541301A (en) |
| BG (1) | BG65849B1 (en) |
| BR (1) | BR0107683A (en) |
| CA (1) | CA2394165C (en) |
| CY (1) | CY1109567T1 (en) |
| CZ (1) | CZ20022411A3 (en) |
| DE (2) | DE60139907D1 (en) |
| DK (2) | DK1257280T3 (en) |
| EE (1) | EE05533B1 (en) |
| ES (2) | ES2332226T3 (en) |
| HK (1) | HK1047248B (en) |
| HU (1) | HUP0204291A3 (en) |
| IL (3) | IL150775A0 (en) |
| ME (1) | ME00292B (en) |
| MX (1) | MXPA02006613A (en) |
| NO (1) | NO335570B1 (en) |
| NZ (1) | NZ520630A (en) |
| PL (1) | PL201878B1 (en) |
| PT (1) | PT1611892E (en) |
| RS (1) | RS52149B (en) |
| RU (2) | RU2275198C2 (en) |
| SI (2) | SI1611892T1 (en) |
| SK (2) | SK287719B6 (en) |
| WO (1) | WO2001052857A1 (en) |
| ZA (2) | ZA200206551B (en) |
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| SI1214076T1 (en) * | 1999-08-31 | 2004-06-30 | Schering Aktiengesellschaft | Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive |
| EP1216713A1 (en) * | 2000-12-20 | 2002-06-26 | Schering Aktiengesellschaft | Compositions of estrogen-cyclodextrin complexes |
| JP2004521951A (en) | 2001-07-13 | 2004-07-22 | シエーリング アクチエンゲゼルシャフト | Combination of drospirenone and estrogen sulfamate for HRT |
| ATE336252T1 (en) * | 2002-03-11 | 2006-09-15 | Janssen Pharmaceutica Nv | CONTINUOUS SULFATASE-INHIBITING PROGESTOGEN CONTAINING HORMONE SUBSTITUTION THERAPY |
| HK1079997A1 (en) * | 2002-04-26 | 2006-04-21 | 舍林股份公司 | Treatment of hypertension in women receiving hormone replacement therapy |
| WO2004041288A1 (en) * | 2002-11-05 | 2004-05-21 | Schering Aktiengesellschaft | Hormone replacement therapy with drospirenone |
| WO2004041289A1 (en) * | 2002-11-05 | 2004-05-21 | Schering Aktiengesellschaft | Cardiovascular protection using anti-aldosteronic progestins |
| US7786101B2 (en) | 2002-11-05 | 2010-08-31 | Bayer Schering Pharma Ag | Cardiovascular protection using anti-aldosteronic progestins |
| BRPI0508612A (en) | 2004-03-10 | 2007-08-14 | Schering Aktiengellschaft | compositions comprising molecularly dispersed drospirenone |
| MY142989A (en) | 2004-03-10 | 2011-02-14 | Bayer Schering Pharma Ag | Stabilised supersaturated solids of lipophilic drugs |
| DE102004023984A1 (en) * | 2004-05-14 | 2005-12-08 | Hf Arzneimittelforschung Gmbh | Film-shaped, orally-administered drug containing estriol |
| US8022053B2 (en) | 2004-11-02 | 2011-09-20 | Bayer Schering Pharma Aktiengesellschaft | Oral solid dosage forms containing a low dose of estradiol |
| WO2007011764A2 (en) * | 2005-07-15 | 2007-01-25 | Bayer Schering Pharma Aktiengesellschaft | Drospirenone containing transdermal drug delivery devices and methods of delivery thereof |
| DE102005056527A1 (en) * | 2005-11-25 | 2007-07-12 | Grünenthal GmbH | Use of a combination of ethinylestradiol and chlormadinone acetate for the manufacture of a medicament |
| US8617597B2 (en) | 2006-07-06 | 2013-12-31 | Bayer Intellectual Property Gmbh | Pharmaceutical composition containing a tetrahydrofolic acid |
| CN101489563A (en) * | 2006-07-06 | 2009-07-22 | 拜耳先灵医药股份有限公司 | Pharmaceutical preparations for contraception and for preventing the risk of congenital malformations |
| DE102007011105A1 (en) | 2007-03-02 | 2008-09-04 | Bayer Schering Pharma Aktiengesellschaft | Mineralcorticoid receptor antagonist for producing drug for permanent treatment of endometriosis, comprises spironolactone, eplerenone and drospirenone |
| CN101623287B (en) * | 2008-07-07 | 2012-02-08 | 天津金耀集团有限公司 | Novel drospirenone analogue medicinal composition for treating menopausal syndrome |
| ES2344675B1 (en) * | 2008-12-19 | 2011-04-28 | Italfarmaco, S.A. | USE OF ESTRIOL IN THE PREPARATION OF A PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF VAGINAL ATROPHY IN WOMEN WITH RISK OF VARIUM VARCOLOGY. |
| UY32836A (en) | 2009-08-12 | 2011-03-31 | Bayer Schering Pharma Ag | STABILIZED PARTICLES THAT INCLUDE 5-METHYL- (6S) -TETRAHYDROPHOLATE |
| US20130137664A1 (en) * | 2010-04-15 | 2013-05-30 | Bayer Intellectual Property Gmbh | Low-dosed solid oral dosage forms for hrt |
| ES2533584T3 (en) * | 2010-04-15 | 2015-04-13 | Bayer Intellectual Property Gmbh | Solid low dose oral dosage forms for TSH |
| US11351122B1 (en) | 2010-07-28 | 2022-06-07 | Laboratorios Leon Farma Sa | Synthetic progestogens and pharmaceutical compositions comprising the same |
| US10849857B2 (en) | 2010-07-28 | 2020-12-01 | Laboratorios Leon Farma Sa | Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same |
| AR081670A1 (en) | 2010-06-29 | 2012-10-10 | Leon Farma Sa Lab | PHARMACEUTICAL COMPOSITION INCLUDING DROSPIRENONE AND ANTI-ECONCEPTIVE KIT |
| US9603860B2 (en) | 2010-07-28 | 2017-03-28 | Laboratorios Leon Farma Sa | Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same |
| JP2014532685A (en) | 2011-11-04 | 2014-12-08 | バイエル・ファルマ・アクチェンゲゼルシャフトＢａｙｅｒ Ｐｈａｒｍａ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | 18-Methyl-6,7-methylene-3-oxo-17-pregna-4-ene-21,17β-carbolactone, pharmaceutical formulations containing said compound and its use in the treatment of endometriosis |
| TW201350122A (en) * | 2012-04-23 | 2013-12-16 | Bayer Pharma AG | Intrauterine use of 18-methyl-15 β , 16 β -methylene-19-nor-20-spirox-4-en-3-ones, intrauterine systems comprising 18-methyl-15 β , 16 β -methylene-19-nor-20-spirox-4-en-3-ones, and use thereof in contraception and gynaecological treatmen |
| UA115576C2 (en) | 2012-12-06 | 2017-11-27 | Байєр Фарма Акцієнгезелльшафт | BENZIMIDASOL DERIVATIVES AS ER4 ANGAGONES |
| TW201607943A (en) | 2013-12-19 | 2016-03-01 | 拜耳製藥公司 | Novel benzimidazole derivatives as EP4 ligands |
| MD3310333T2 (en) | 2015-06-18 | 2020-06-30 | Estetra Sprl | Orodispersible dosage unit containing an estetrol component |
| CA3178291A1 (en) | 2016-08-05 | 2018-04-12 | Estetra Srl | Method for the management of dysmenorrhea and menstrual pain |
| CN110809473A (en) * | 2017-06-01 | 2020-02-18 | 延世大学校产学协力团 | Pharmaceutical composition for preventing or treating bone-related diseases |
| TWI801561B (en) | 2018-04-19 | 2023-05-11 | 比利時商依思特拉私人有限責任公司 | Compounds and their uses for alleviating menopause-associated symptoms |
| DK3781171T3 (en) * | 2018-04-19 | 2022-05-02 | Estetra Srl | COMPOSITIONS AND THEIR APPLICATIONS FOR THE RELIEF OF MENOPAUSE-ASSOCIATED SYMPTOMS |
| TWI893101B (en) | 2020-04-16 | 2025-08-11 | 比利時商埃斯特拉有限責任公司 | Contraceptive compositions with reduced adverse effects |
| CN115813937B (en) * | 2022-12-01 | 2025-04-11 | 南通联亚药业股份有限公司 | A stable pharmaceutical composition comprising drospirenone and estradiol and a preparation method thereof |
| CN118356456A (en) * | 2024-04-17 | 2024-07-19 | 且安生物科技有限责任公司 | A method for preparing an anti-inflammatory nest-protecting herbal extract |
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| DE3022337A1 (en) * | 1980-06-11 | 1982-01-07 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | Compsns. for contraception or treatment of gynaecological disorders - contg. 6 beta, 7 beta; 15 delta, 16 beta-di:methylene-3-oxo-4-androstene-17(beta-1')-spiro-5'-per:hyd- ro-furan-2'-one |
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| JP2859919B2 (en) * | 1990-03-15 | 1999-02-24 | 旭化成工業株式会社 | Method for improving dissolution of poorly soluble drugs |
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| JP4022269B2 (en) * | 1995-05-26 | 2007-12-12 | 協和醗酵工業株式会社 | Pharmaceutical composition |
| US5922349A (en) * | 1995-09-28 | 1999-07-13 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
| KR100518102B1 (en) * | 1996-07-26 | 2005-10-04 | 와이어쓰 | Monophasic contraceptive kit comprising a combination of a progestin and estrogen |
| AU3961697A (en) * | 1996-07-26 | 1998-02-20 | American Home Products Corporation | Oral contraceptive |
| DE19633685C1 (en) * | 1996-08-12 | 1997-10-09 | Schering Ag | Production of drospirenone useful as steroidal agent |
| DE19654609A1 (en) * | 1996-12-20 | 1998-06-25 | Schering Ag | Therapeutic progestogens for the treatment of premenstrual dysphoric disorder |
| JPH10182701A (en) * | 1996-12-26 | 1998-07-07 | Sanei Toka Kk | Powder having improved release property and its production |
| US6045829A (en) * | 1997-02-13 | 2000-04-04 | Elan Pharma International Limited | Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers |
| SI1214076T1 (en) * | 1999-08-31 | 2004-06-30 | Schering Aktiengesellschaft | Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive |
-
2001
- 2001-01-18 AT AT05076969T patent/ATE442147T1/en active
- 2001-01-18 WO PCT/IB2001/000041 patent/WO2001052857A1/en not_active Ceased
- 2001-01-18 PT PT05076969T patent/PT1611892E/en unknown
- 2001-01-18 EE EEP200200401A patent/EE05533B1/en unknown
- 2001-01-18 CZ CZ20022411A patent/CZ20022411A3/en unknown
- 2001-01-18 SK SK1032-2002A patent/SK287719B6/en not_active IP Right Cessation
- 2001-01-18 HU HU0204291A patent/HUP0204291A3/en unknown
- 2001-01-18 HK HK02109001.6A patent/HK1047248B/en not_active IP Right Cessation
- 2001-01-18 RU RU2002122113/15A patent/RU2275198C2/en active
- 2001-01-18 SI SI200130947T patent/SI1611892T1/en unknown
- 2001-01-18 SK SK5025-2011A patent/SK288129B6/en not_active IP Right Cessation
- 2001-01-18 AT AT01900579T patent/ATE305789T1/en active
- 2001-01-18 ES ES05076969T patent/ES2332226T3/en not_active Expired - Lifetime
- 2001-01-18 EP EP01900579A patent/EP1257280B1/en not_active Revoked
- 2001-01-18 ME MEP-2008-380A patent/ME00292B/en unknown
- 2001-01-18 CN CN2010102885016A patent/CN101934078A/en active Pending
- 2001-01-18 PL PL356987A patent/PL201878B1/en unknown
- 2001-01-18 DK DK01900579T patent/DK1257280T3/en active
- 2001-01-18 AU AU2541301A patent/AU2541301A/en active Pending
- 2001-01-18 NZ NZ520630A patent/NZ520630A/en not_active IP Right Cessation
- 2001-01-18 SI SI200130434T patent/SI1257280T1/en unknown
- 2001-01-18 DE DE60139907T patent/DE60139907D1/en not_active Expired - Lifetime
- 2001-01-18 CN CN01803878A patent/CN1395488A/en active Pending
- 2001-01-18 DE DE60113809T patent/DE60113809T2/en not_active Expired - Lifetime
- 2001-01-18 JP JP2001552904A patent/JP5128743B2/en not_active Expired - Lifetime
- 2001-01-18 AU AU2001225413A patent/AU2001225413B2/en not_active Expired
- 2001-01-18 IL IL15077501A patent/IL150775A0/en active IP Right Grant
- 2001-01-18 DK DK05076969T patent/DK1611892T3/en active
- 2001-01-18 CA CA2394165A patent/CA2394165C/en not_active Expired - Lifetime
- 2001-01-18 ES ES01900579T patent/ES2247054T3/en not_active Expired - Lifetime
- 2001-01-18 BR BR0107683-3A patent/BR0107683A/en not_active Application Discontinuation
- 2001-01-18 RS YU54602A patent/RS52149B/en unknown
- 2001-01-18 EP EP05076969A patent/EP1611892B1/en not_active Expired - Lifetime
- 2001-01-18 MX MXPA02006613A patent/MXPA02006613A/en active IP Right Grant
- 2001-01-18 KR KR1020027009259A patent/KR100747965B1/en not_active Expired - Lifetime
- 2001-01-18 KR KR1020077010304A patent/KR100913910B1/en not_active Expired - Lifetime
-
2002
- 2002-06-20 NO NO20022966A patent/NO335570B1/en not_active IP Right Cessation
- 2002-07-12 BG BG106915A patent/BG65849B1/en unknown
- 2002-07-16 IL IL150775A patent/IL150775A/en unknown
- 2002-08-15 ZA ZA2002/06551A patent/ZA200206551B/en unknown
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2005
- 2005-09-07 AU AU2005209600A patent/AU2005209600B2/en not_active Expired
- 2005-12-27 RU RU2005140938/15A patent/RU2402331C2/en active
-
2006
- 2006-02-13 ZA ZA2006/01285A patent/ZA200601285B/en unknown
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2008
- 2008-04-29 IL IL191131A patent/IL191131A/en active IP Right Grant
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2009
- 2009-02-12 JP JP2009030542A patent/JP5563227B2/en not_active Expired - Lifetime
- 2009-12-09 CY CY20091101285T patent/CY1109567T1/en unknown
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